Hsp70 in Redox Homeostasis

Abstract

Cellular redox homeostasis is precisely balanced by generation and elimination of reactive oxygen species (ROS). ROS are not only capable of causing oxidation of proteins, lipids and DNA to damage cells but can also act as signaling molecules to modulate transcription factors and epigenetic pathways that determine cell survival and death. Hsp70 proteins are central hubs for proteostasis and are important factors to ameliorate damage from different kinds of stress including oxidative stress. Hsp70 members often participate in different cellular signaling pathways via their clients and cochaperones. ROS can directly cause oxidative cysteine modifications of Hsp70 members to alter their structure and chaperone activity, resulting in changes in the interactions between Hsp70 and their clients or cochaperones, which can then transfer redox signals to Hsp70-related signaling pathways. On the other hand, ROS also activate some redox-related signaling pathways to indirectly modulate Hsp70 activity and expression. Post-translational modifications including phosphorylation together with elevated Hsp70 expression can expand the capacity of Hsp70 to deal with ROS-damaged proteins and support antioxidant enzymes. Knowledge about the response and role of Hsp70 in redox homeostasis will facilitate our understanding of the cellular knock-on effects of inhibitors targeting Hsp70 and the mechanisms of redox-related diseases and aging.

Keywords: Hsp70; ROS; cysteine modifications; glutathionylation; oxidative stress; redox homeostasis.

Figure 1

Scheme of Hsp70 in redox homeostasis. Reactive oxygen species (ROS) often cause extensive cysteine modifications of proteins and disturb proteostasis, which can activate the heat shock response (HSR) and Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathways by activation of heat shock transcription factor 1 (Hsf1) and redox-sensitive transcription factor Nrf2. ROS also widely modify different cellular signaling pathways. Hsp70s are involved in redox homeostasis in several aspects: (a) ROS can cause cysteine modifications of Hsp70s to modify their functions; (b) activation of Hsf1 and Nrf2 elevate expression of HSP70s; (c) Hsp70s work as central hubs in the protein quality control network to maintain proteostasis, including eliminating oxidized proteins and regulating activity, expression and degradation of antioxidant enzymes to contribute to redox homeostasis; and (d) Hsp70s are involved in redox-related signaling pathways, leading to phosphorylation or upregulated expression of Hsp70s.

Figure 2

Crystal structures of human HspA1A. The nucleotide-binding domain (NBD) in the ADP-bound state (PDB code 3AY9) and the substrate-binding domain (SBD, PDB code 4PO2) are shown. The dashed line represents the flexible linker between the NBD and SBD. The SBD contains a β-sandwich substrate-binding subdomain (SBDβ) and an α-helical lid subdomain (SBDα). The five Cys residues are labeled in green. Figure reproduced from ref. [52].

Figure 3

Glutathionylation of the cysteine residues of Hsp70 family members in HeLa cells with or without diamide treatment detected by mass spectrometry. Figure adapted from ref. [52].

Figure 4

The most conserved Cys residue in Hsp70 homologues. The conserved Cys is indicated by the green dashed box. In each line the last number indicates the position of the last residue in the corresponding Hsp70 homologue.